The aim of the experiments is to continue our studies into the hormonal and neural regulation of glucose production (glycogenolysis and gluconeogenesis) in the overnight fasted conscious dog. Specifically we will focus on 1) the way in which glycogenolysis and gluconeogenesis affect one another in vivo, 2) the way in which certain of the counterregulatory hormones (glucagon and epinephrine; cortisol and epinephrine) interact to control glycogenolysis and gluconeogenesis, 3) the extent to which insulin can alter gluconeogenesis in vivo and the time it takes to do so, 4) the impact of hepatic denervation on muscle glucose disposal and the mechanism by which such an effect comes about, the 5) the control of glucagon secretion and action during hypoglycemia. We will carry out studies using 18h fasted conscious dogs fitted with a variety of sampling and infusion catheters and prepared surgically (i.e. adrenalectomy, hepatic and pancreatic denervation) as required by the protocol. Glucose metabolism will be assessed using A-V difference (gut, liver, kidney, hindlimb, pancreas) and tracer (3H-glucose) techniques. Gluconeogenesis will also be assessed using A-V difference and tracer (14C alanine) techniques. The rates of renal and hepatic uptake of gluconeogenic precursors will be measured over time. In addition at the end of the study liver biopsies will be taken and the techniques of Giaccari and Rossetti will be used to assess the steady state hepatic gluconeogenic rate. We will also determine gluconeogenic enzyme and G-6-P levels in the terminal liver biopsies. Once the gluconeogenic rate is known we can estimate net glycogenolysis since we will also know the rates of net hepatic glucose output, net hepatic lactate production, and hepatic glucose oxidation. The hormonal conditions will be controlled in most studies using somatostatin, adrenalectomy or substrate clamps so that we can modify the variable of concern in isolation. In other studies substrate levels will be controlled and the hormone levels will be allowed to change. The answers obtained by the proposed studies should enhance our understanding of the control of glucose production and pancreatic function in vivo.